Trypanosoma rangeli protein tyrosine phosphatase is associated with the parasite's flagellum

Prestes, Elisa Beatriz; Bayer-Santos, Ethel; Stoco, Patrícia Hermes; Sincero, Thaís Cristine Marques; Wagner, Glauber; Umaki, Adriana Castilhos Souza; Fragoso, Stênio Perdigão; Bordignon, Juliano; Steindel, Mário; Grisard, Edmundo Carlos

doi:10.1590/s0074-02762012000600002

Cited by 7 publications

(3 citation statements)

References 27 publications

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“…Yet inhibition of TcPTP2 may also have therapeutic benefits. Its ortholog in Trypanosoma rangeli (TrPTP2) was shown to be associated with the parasite's flagellum and may play a role in modulating the phosphorylation state of proteins that regulate its structure [72]. In any case, the development of highly specific inhibitors, facilitated by the crystal structure of TcPTP1, will ultimately resolve any lingering uncertainty about the validity of this enzyme as a molecular target for the treatment of Chagas’ disease.…”

Section: Resultsmentioning

confidence: 99%

Structure of the Trypanosoma cruzi protein tyrosine phosphatase TcPTP1, a potential therapeutic target for Chagas’ disease

Lountos

Tropea

Waugh

2013

Molecular and Biochemical Parasitology

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Chagas’ disease, a neglected tropical affliction transmitted by the flagellated protozoan Trypanosoma cruzi, is prevalent in Latin America and affects nearly 18 million people worldwide, yet few approved drugs are available to treat the disease. Moreover, the currently available drugs exhibit severe toxicity or are poorly effective in the chronic phase of the disease. This limitation, along with the large population at risk, underscores the urgent need to discover new molecular targets and novel therapeutic agents. Recently, the T. cruzi protein tyrosine phosphatase TcPTP1 has been implicated in the cellular differentiation and infectivity of the parasite and is therefore a promising target for the design of novel anti-parasitic drugs. Here, we report the X-ray crystal structure of TcPTP1 refined to a resolution of 2.18 Å, which provides structural insights into the active site environment that can be used to initiate structure-based drug design efforts to develop specific TcPTP1 inhibitors. Potential strategies to develop such inhibitors are also discussed.

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Section: Resultsmentioning

confidence: 99%

Structure of the Trypanosoma cruzi protein tyrosine phosphatase TcPTP1, a potential therapeutic target for Chagas’ disease

Lountos

Tropea

Waugh

2013

Molecular and Biochemical Parasitology

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“…Nevertheless, the functional role of LmPP2C has yet to be established (Escalona-Montaño et al, 2017). In other trypanosomatid parasites, such as Trypanosoma rangeli, a PTP was associated with the parasite flagellum, although its function is unknown (Prestes et al, 2012). In most of these parasites, the PP2C enzymes are mainly located in the cytosol.…”

Section: Discussionmentioning

confidence: 99%

Protein Serine/Threonine Phosphatase Type 2C of Leishmania mexicana

Escalona‐Montaño

Zuñiga-Fabián²,

Cabrera

et al. 2021

Front. Cell. Infect. Microbiol.

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Protein phosphorylation and dephosphorylation are increasingly recognized as important processes for regulating multiple physiological mechanisms. Phosphorylation is carried out by protein kinases and dephosphorylation by protein phosphatases. Phosphoprotein phosphatases (PPPs), one of three families of protein serine/threonine phosphatases, have great structural diversity and are involved in regulating many cell functions. PP2C, a type of PPP, is found in Leishmania, a dimorphic protozoan parasite and the causal agent of leishmaniasis. The aim of this study was to clone, purify, biochemically characterize and quantify the expression of PP2C in Leishmania mexicana (LmxPP2C). Recombinant LmxPP2C dephosphorylated a specific threonine (with optimal activity at pH 8) in the presence of the manganese divalent cation (Mn+2). LmxPP2C activity was inhibited by sanguinarine (a specific inhibitor) but was unaffected by protein tyrosine phosphatase inhibitors. Western blot analysis indicated that anti-LmxPP2C antibodies recognized a molecule of 45.2 kDa. Transmission electron microscopy with immunodetection localized LmxPP2C in the flagellar pocket and flagellum of promastigotes but showed poor staining in amastigotes. Interestingly, LmxPP2C belongs to the ortholog group OG6_142542, which contains only protozoa of the family Trypanosomatidae. This suggests a specific function of the enzyme in the flagellar pocket of these microorganisms.

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“…The heterogeneous staining pattern of the parasites may be due to different development stages of the parasite, since the culture was not synchronized. In other Trypanosomatid parasites, such as Trypanosoma rangeli , a PTP was reported to be associated with the parasite flagellum, yet the function remains unknown (Prestes et al 2012). In most of these cells, the PP2C enzymes are mainly localized in the cytosol, and in the case of T. gondii , the parasite also uses secretion from the rhoptries during invasion, in order to deliver a parasite-derived PP2C into the host cell and target it to the host nucleus (Gilbert et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Protein phosphatase PP2C in the flagellum of Leishmania major: cloning and characterization

et al. 2017

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The main goal of this work consisted in cloning, purifying and characterizing a protein phosphatase 2C (PP2C) from promastigotes of Leishmania major. The gene was cloned and amplified by PCR using specific oligonucleotides and the recombinant protein was purified by affinity chromatography. The peak with maximal protein concentration was analysed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and revealed a protein of 44·9 kDa with PP2C activity. This activity was dependent on divalent cations (Mg +2 and Mn +2 ) and was optimal at pH of 8·5, using phosphothreonine as the substrate. Sanguinarine inhibited the activity of the recombinant LmPP2C, while protein tyrosine phosphatase inhibitors had no effect. The recombinant LmPP2C was used to generate polyclonal antibodies. These antibodies recognized a protein of 44·9 kDa in different Leishmania species; the LmPP2C was localized in the flagellar pocket and the flagellum of promastigotes.

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Trypanosoma rangeli protein tyrosine phosphatase is associated with the parasite's flagellum

Cited by 7 publications

References 27 publications

Structure of the Trypanosoma cruzi protein tyrosine phosphatase TcPTP1, a potential therapeutic target for Chagas’ disease

Structure of the Trypanosoma cruzi protein tyrosine phosphatase TcPTP1, a potential therapeutic target for Chagas’ disease

Protein Serine/Threonine Phosphatase Type 2C of Leishmania mexicana

Protein phosphatase PP2C in the flagellum of Leishmania major: cloning and characterization

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